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J. Exp. Med.,
Volume 188, Number 10, November 16, 1998 1795-1802
By
§§
From the * Graduate Institute of Microbiology and Immunology, National Yang-Ming University,
Taipei 11217, Taiwan; the Fas and Fas-associated death domain (FADD) play a critical role in the homeostasis of different
cell types. The regulation of Fas and FADD-mediated cell death is pivotal to many physiological functions. The activation of T lymphocytes by concanavalin A (Con A) inhibited Fas-mediated cell death. We identified that among the several activation signals downstream of Con A
stimulation, mitogen-activated protein (MAP) kinase kinase (MKK) was the major kinase pathway that antagonized Fas-triggered cell death. MKK1 suppressed FADD- but not caspase-3-
induced apoptosis, indicating that antagonism occurred early along the Fas-initiated apoptotic cascade. We further demonstrated that activation of MKK1 led to expression of FLIP, a specific
inhibitor of FADD. MKK1 inhibition of FADD-induced cell death was abrogated if induction
of FLIP was prevented, indicating that FLIP mediates MKK1 suppression of FADD-mediated
apoptosis. Our results illustrate a general mechanism by which activation of MAP kinase attenuates apoptotic signals initiated by death receptors in normal and transformed cells.
Institute of Molecular Biology, Academia Sinica, Nankang, Taipei
11529, Taiwan; and the § Graduate Institute of Microbiology, National Taiwan University School of
Medicine, Taipei 10018, Taiwan
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